The proposed research project will examine the relationship of lysosomal enzyme activity to cancer chemotherapy-induced cell death. Enzyme activity will be measured in vitro at various intervals following the in vivo administration of either nitrogen mustard or hydroxyurea to rats. Chemotherapy-induced alterations in lysosomal enzyme activity will be studied in (a) continuously dividing normal cell populations which are sensitive to the necrogenic effects of these agents and (b) normally quiescent cells which have been stimulated to divide, which are resistant to the cytocidal actions of antitumor drugs. Changes in lysosomal enzyme activity will be correlated with the capacity of these drugs to inhibit DNA synthesis, induce a loss of radioactive DNA from tissues prelabeled with 125I-IudR, and to produce histological evidence of cell death. Finally, the ability of cycloheximide to protect intestinal epithelial cells against the necrogenic effects of nitrogen mustard and hydroxyurea will be correlated with its ability to affect the synthesis of lysosomal enzymes in these cells. BIBLIOGRAPHIC REFERENCE: A.M. Cohen. The Disposition of Ftorafur in Rats After Intravenous Administration. Drug Metabolism and Disposition, July-August 1975, in press.